CN1107702A - Methods of inhibiting ovarian dysgenesis delayed puberty, or sexual infantilism - Google Patents
Methods of inhibiting ovarian dysgenesis delayed puberty, or sexual infantilism Download PDFInfo
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- CN1107702A CN1107702A CN94119729A CN94119729A CN1107702A CN 1107702 A CN1107702 A CN 1107702A CN 94119729 A CN94119729 A CN 94119729A CN 94119729 A CN94119729 A CN 94119729A CN 1107702 A CN1107702 A CN 1107702A
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- acid
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- chemical compound
- infantilism
- raloxifene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Hydrogenated Pyridines (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Tea And Coffee (AREA)
- Adjustment And Processing Of Grains (AREA)
- Compounds Of Unknown Constitution (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Tires In General (AREA)
- Control Of Metal Rolling (AREA)
Abstract
A method of inhibiting ovarian dysgenesis, delayed puberty, or sexual infantilism comprising administering to a human in need thereof an effective amount of a compound having the formula (I) wherein R1 and R3 are independently hydrogen, -CH3, wherein Ar is optionally substituted phenyl; R2 is selected from the group consisting of pyrrolidine, hexamethyleneamino, and piperidino; or a pharmaceutically acceptable salt of solvate thereof.
Description
The girl that delayed pubertas was defined under age of mean age two standard deviations when being higher than pubarche lacks sexually matured physical manifestations.Disease according to luteinizing hormone releasing hormone (LHRH) pulsation generator, pituitary gland or ovary effect are exerted an influence can further be subdivided into several classifications with this delayed pubertas.It comprises the special property sent out (body constitution) growth and delayed pubertas, the too much property of hypogonadotropic hypogonadism and promoting sexual gland hormone hypogonadism.
The special property growth delay of sending out generally is applicable to the girl who spontaneously adolesces after 12 years old at normal age.In most of the cases, treating with LHRH within back 1 year or within promoting sexual gland hormone and estradiol concentration began spontaneously to raise back 1 year, first sign of secondary growth can occur.Like this, the child has realized whole genetic potentials of her height usually, and reaches the completeness maturation, but needs the longer time than the normal person.After pubarche, suffer from the patient's of body constitution growth and delayed pubertas the speed of growth and just recover normal.The character and the order of severity of disease depended in the treatment of delayed pubertas.The estrogen that the treatment of girl's delayed pubertas is generally included three months courses of treatment replenishes, so that cause the maturation of secondary feature.
The insufficient pollex secretion of LHRH and the follicule-stimulating hormone (FSH) (FSH) that is produced and LH lack also can cause sex infantilism.LHRH lacks may belong to heredity or developmental defect, or may be due to tumor, inflammatory reaction, vascular lesion or wound.The various cause of disease and the obstacles relevant with this disease are arranged.Promoting sexual gland hormone lacks and need treat with the complementing estrogen therapy under the age near the normal age of pubarche, and proceeds to and reach fertility.
The estrogen secretion of constitutional ovarian failure and weakening can cause the negative feedback that reduces and the LH and the FSH concentration of rising.This is called the too much property of promoting sexual gland hormone hypogonadism.It generally shows as Turner syndrome, and can or begin in 13 years old with replenishing the estradiol hormone therapy, so that begin secondary growth at the suitable age 12.
Ovarian agenesis can be caused by many factors.Development of ovary depletion or ovarian agenesis usually with the childhood period hypopituitarism relevant.Thyroid and adrenocortical shortage are usually with the replacement therapy compensation, and sexual development decline estrin treatment.
Treatment with hormonal supplementation under the adolescence normal age may have some shortcomings.In addition, high dose estrogen can be accelerated tall girl's epiphysis bone closure, seldom uses it owing to the side effect relevant with this high dose scheme.Therefore, need to seek the new method that treats and/or prevents above-mentioned disease.
The invention provides the method that suppresses ovarian agenesis, delayed pubertas or sex infantilism, comprise that the people to needs uses formula I chemical compound and the acceptable salt of medicine and the solvate of effective dose.
R wherein
1And R
3Hydrogen, CH respectively do for oneself
3,
(C
1-C
6Alkyl) or
, wherein Ar is the phenyl that replaces arbitrarily;
R
2Be selected from pyrrolidinyl, hexamethyleneimino and piperidino.
The present invention relates to find one group of 2-phenyl-3-aroyl benzothiophenes (benzothiophene kind) of selecting, promptly the formula I chemical compound can be used for suppressing ovarian agenesis, delayed pubertas or sex infantilism.The enforcement of using method provided by the invention is by using formula I chemical compound or the acceptable salt of its medicine or the solvate of the dosage that can suppress ovarian agenesis, delayed pubertas or the thin young type of property or its simultaneous phenomenon effectively for the people who needs.Term suppresses to be restricted to comprise its common acceptable meaning, promptly comprises to the people's preventive usage that suffers described disease or its symptom, and controls and/or treat one of described disease or symptom.Therefore, as required, the inventive method comprises therapeutic treatment and/or prophylactic treatment.
The compounds of this invention raloxifene (Raloxifene) is R wherein
1And R
3Be hydrogen and R
2Be the hydrochlorate of the formula I chemical compound of piperidino, and this chemical compound is that nuclear is regulated molecule.Raloxifene has shown with estrogen receptor and combines, and has been considered to a kind of like this molecule at first: be antiestrogenic on its function and the pharmacology promptly, promptly it has the ability that blocking-up estrogen activates uterine cancer cell and estrogen-dependent type breast carcinoma.In fact, raloxifene has been blocked estrogenic effect in some cell; Yet in other kinds cell, raloxifene activates identical gene and shows same pharmacology with estrogen, for example osteoporosis, hyperlipemia.As a result, raloxifene is known as and has excitement-estrogen antagonist of antagonism double properties.With opposite by estrogen-estrogen receptor complex activation and/or suppressor gene, raloxifene is shown and be different from the feature of estrogenic uniqueness, is considered at present be activated uniquely and/or suppressed the range gene function by raloxifene-estrogen receptor complex.Therefore, although raloxifene and estrogen utilization and compete same receptor, the pharmacology result of their regulator gene is difficult to predict, and differs from one another.
Usually The compounds of this invention can be prepared with common excipient, diluent or carrier, and be pressed into and be convenient to oral tablet or be mixed with elixir or solution; Perhaps by intramuscular or intravenous route administration.This chemical compound can percutaneous dosing, and can be mixed with dosage forms such as continuing release.
Employed chemical compound can be by set method (US4 for example, 133,814,4,418,068 and 4,380, the method described in 635, these patents are incorporated herein by reference) preparation in the inventive method.Generally, this method is with having 6-hydroxyl and 2-(4-hydroxyphenyl) benzo [b] thiophene begin.With initial compounds protection, acyl groupization and deprotection, form the formula I chemical compound.The preparation example of these chemical compounds is provided in above-mentioned United States Patent (USP).The phenyl that replaces comprises by C
1-C
6Alkyl, C
1-C
4The phenyl that alkoxyl, hydroxyl, nitro, chlorine, fluorine or three (chlorine or fluorine) methyl replace once or twice.
The chemical compound that is used for the inventive method can generate the bronsted lowry acids and bases bronsted lowry addition salts that pharmaceutically are suitable for various organic and mineral acids and alkali reaction, and pharmaceutically the bronsted lowry acids and bases bronsted lowry addition salts of Shi Yonging comprises salt suitable on the physiology that is generally used for pharmaceutical chemistry.Described salt also is a part of the present invention.The mineral acid commonly used that generates described salt comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, hypophosphoric acid etc.Salt also can be obtained by organic acid, alkanoic acid, hydroxyl alkane acid and hydroxyl chain docosandioic acid that adaptable organic acid has for example aliphatic one and dicarboxylic acids, phenyl to replace, aromatic acid, aliphatic and aromatic sulphonic acid.The described salt that pharmaceutically is suitable for comprises acetate, phenylacetic acid salt, trifluoroacetate, acrylates, Ascorbate, benzoate, chloro benzoate, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, ar-Toluic acid salt, o-acetyl-p-methoxybenzoic acid salt, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyric acid salt, beta-hydroxy-butanoic acid salt, butine-1, the 4-diacid salt, hexin-1, the 4-diacid salt, caprate, caprylate, chloride, cinnamate, citrate, formates, fumarate, hydroxyl acetate, enanthate, hippurate, lactate, malate, maleate, hydroxymaleic acid salt, malonate, mandelate, mesylate, nicotinate, .gamma.-pyridinecarboxylic acid salt, nitrate, oxalates, phthalate, terephthalate, phosphate, dibasic alkaliine, dihydric phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionic acid salt, Salicylate, sebacate, succinate, suberate, sulfate, disulfate, pyrosulfate, sulphite, bisulfites, sulfonate, benzene sulfonate, brosylate, closilate, esilate, the 2-isethionate, mesylate, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, tosilate, xylenesulfonate, tartrate etc.Preferred salt is hydrochlorate.
Pharmaceutically the acid-addition salts of Shi Yonging usually by the formula I chemical compound with etc. mole or excessive acid reaction and make.Usually make reactant in mutual solvent such as ether or benzene, carry out chemical combination.Salt was separated out from solution in 10 days about 1 hour usually, separated after filtration, or removed according to a conventional method and desolvate.
Be generally used for the salifiable alkali of shape and comprise ammonium hydroxide, alkali metal and alkaline earth metal hydroxide, carbonate, and aliphatic primary, the second month in a season and tertiary amine, aliphatic diamine.Especially the alkali that is suitable in the preparation addition salts comprises ammonium hydroxide, potassium carbonate, methylamine, diethylamine, 1 and cyclohexylamine.
Compare with its derived compounds, pharmaceutically the salt of Shi Yonging can improve solubility property usually, therefore usually more is applicable to be mixed with as liquid agent or Emulsion.
Pharmaceutical formulation can prepare by methods known in the art.For example, this chemical compound and common excipient, diluent or carrier are prepared, and made tablet, capsule, suspension, powder etc.The example that is applicable to excipient, diluent and the carrier of above-mentioned preparation comprises as follows: filler and extender such as starch, sugar, mannitol and silicon derivative; Binding agent such as carboxymethyl cellulose and other cellulose derivatives, alginate, gelatin and polyvinylpyrrolidone; Wetting agent such as glycerol; Disintegrating agent such as calcium carbonate and sodium bicarbonate; Retardance lytic agent such as paraffin; Absorption enhancer such as quaternary ammonium compound; Surfactant such as spermol, glyceryl monostearate; Absorption carrier such as Kaolin and bentonite; Lubricant such as Talcum, calcium stearate and magnesium stearate, and solid-state poly-ethohexadiol.
This chemical compound also can be mixed with is convenient to oral elixir or solution, or is suitable for the solution of parenterai administration, for example through intramuscular, subcutaneous or intravenous route administration.In addition, this chemical compound also is fit to be mixed with dosage forms such as lasting release very much.Said preparation also can constitute like this, makes them only or be preferably in the specific part of intestinal, may discharge effective ingredient in the regular hour.Coating, peplos and protection substrate can be made by for example polymeric material or wax:
According to the present invention, the given dose that suppresses the required formula I chemical compound of ovarian agenesis, delayed pubertas or sex infantilism or simultaneous phenomenon will depend on that the order of severity of disease, medicine are to approach with by the nursing correlative factor that the doctor determined.Usually, acceptable and effective daily dose was about 0.1 to about 1000mg/ day, more preferably about 50 to about 200mg/ days.With once a day to about three times or divide more times that this dosed administration is given the patient of needs as required, so that treat ovarian agenesis, delayed pubertas or sex infantilism or its symptom effectively.In addition, other delivery of active ingredients can be given the people who needs, as LHRH agonist or progestogen.
Because the medicine of taking has base (as the piperidino ring), therefore preferably take the formula I chemical compound of acid-addition salts form usually.Oral The compounds of this invention is favourable to the user.For this purpose, following oral dosage form is suitable for.
Preparation
In following preparation, " active component " is meant the formula I chemical compound.
Preparation 1: gelatine capsule
Prepare hard gelatin capsule with following ingredients:
Become component (mg/ capsule)
Active component 0.1-1000
Starch, NF 0-650
Flowable Powdered starch 0-650
Silicon fluid (350 centistoke) 0-15
Each composition is mixed,, be packed into hard gelatin capsule by No. 45 sieves of the U.S..
The concrete raloxifene capsule preparations example that has prepared comprise as follows those:
Preparation 2: raloxifene capsule
Become component (mg/ capsule)
Raloxifene 1
Starch, NF 112
Flowable starch powder 225.3
Silicon fluid (350 centistoke) 1.7
Preparation 3: raloxifene capsule
Become component (mg/ capsule)
Raloxifene 5
Starch, NF 108
Flowable starch powder 225.3
Silicon fluid (350 centistoke) 1.7
Preparation 4: raloxifene capsule
Become component (mg/ capsule)
Raloxifene 10
Starch, NF 103
Flowable starch powder 225.3
Silicon fluid (350 centistoke) 1.7
Preparation 5: raloxifene capsule
Become component (mg/ capsule)
Raloxifene 50
Starch, NF 150
Flowable starch powder 397
Silicon fluid (350 centistoke) 3.0
Can reasonably change above-mentioned concrete preparation.
Prepare tablet with following ingredients:
Preparation 6: tablet
Become component (mg/ sheet)
Active component 0.1-1000
Microcrystalline Cellulose 0-650
Atomization silicon dioxide 0-650
Stearic acid 0-15
Each composition is mixed, be pressed into tablet.
In addition, every tablet of tablet that contains 0.1~1000mg active component prepares by the following method:
Preparation 7: tablet
Become component (mg/ sheet)
Active component 0.1-1000
Starch 45
Microcrystalline Cellulose 35
Polyvinylpyrrolidone (10% aqueous solution) 4
Sodium carboxymethyl cellulose 4.5
Magnesium stearate 0.5
Talcum 1
Active component, starch and cellulose are also mixed fully by No. 45 sieves of the U.S..The powder mixes of polyvinylpyrrolidonesolution solution and gained is then by No. 14 sieves of the U.S..The granule of preparation is sieved for No. 18 in 50 °~60 ℃ dryings and by the U.S..Sodium carboxymethyl cellulose, magnesium stearate and the Talcum that will sieve for No. 60 by the U.S. in advance adds in this granule then, with granule tabletting on tablet machine, obtains tablet after the mixing.
Every 5ml contains the suspension of 0.1-1000mg medicine and presses the method preparation:
Preparation 8: suspension
Become component (mg/5ml)
Active component 0.1-1000mg
Sodium carboxymethyl cellulose 50mg
Syrup 1.25mg
Benzoic acid solution 0.10ml
Flavoring agent is an amount of
Coloring agent is an amount of
Purified water is to 5ml
Medicine is sieved for No. 45 by the U.S., and be mixed and made into the pastel of mixing well with sodium carboxymethyl cellulose and syrup.Benzoic acid solution, flavoring agent and coloring agent dilute with a part of water, and under agitation add in the pastel.Add enough water then to volume required.
Experimental procedure
Select 5 to 50 women to be used for clinical research.These women's age is between 12 to 18, and has been suffered from ovarian agenesis, delayed pubertas or sex infantilism by diagnosis, but in addition they have good condition of health.This research is provided with the placebo matched group, soon the women is divided into two groups, and a winding is subjected to activating agent of the present invention, and another winding is subjected to placebo.Women's by oral route of test group is accepted the 50-200mg activating agent every day.This treatment continues 2-12 month.Keep writing down accurately two groups morbid state and symptom thereof, and when research finishes, compare these results.Result between more every group membership, and will be that the state that each patient gives a report is compared before each patient's result and the research beginning.
To the ovarian agenesis, delayed pubertas or the sex infantilism that are used for above-mentioned research and/or the positivity effect of one or more simultaneous phenomenons, the practicality of The compounds of this invention can be described by The compounds of this invention.
Claims (4)
1, is applicable to the pharmaceutical composition that suppresses ovarian agenesis, delayed pubertas or sex infantilism, comprises following formula: compound or acceptable salt of its medicine or solvate as active component
(Ⅰ)
2, the pharmaceutical composition of claim 1, wherein said chemical compound are its hydrochlorates.
3, the pharmaceutical composition of claim 1, wherein said compositions is suitable for preventive administration.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US170,946 | 1993-12-21 | ||
US08/170,946 US5451589A (en) | 1993-12-21 | 1993-12-21 | Methods of inhibiting ovarian dysgenesis, delayed puberty, or sexual infantilism |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1107702A true CN1107702A (en) | 1995-09-06 |
Family
ID=22621923
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN94119729A Pending CN1107702A (en) | 1993-12-21 | 1994-12-19 | Methods of inhibiting ovarian dysgenesis delayed puberty, or sexual infantilism |
Country Status (19)
Country | Link |
---|---|
US (4) | US5451589A (en) |
EP (1) | EP0662325B1 (en) |
JP (1) | JPH07215867A (en) |
KR (1) | KR950016733A (en) |
CN (1) | CN1107702A (en) |
AT (1) | ATE207748T1 (en) |
AU (1) | AU8153294A (en) |
CA (1) | CA2138500A1 (en) |
CZ (1) | CZ321694A3 (en) |
DE (1) | DE69428877T2 (en) |
DK (1) | DK0662325T3 (en) |
ES (1) | ES2162844T3 (en) |
HU (1) | HUT71228A (en) |
IL (1) | IL112049A0 (en) |
NO (1) | NO944917L (en) |
PT (1) | PT662325E (en) |
RU (1) | RU94045272A (en) |
SI (1) | SI0662325T1 (en) |
ZA (1) | ZA9410097B (en) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US6515009B1 (en) | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5847007A (en) | 1993-05-13 | 1998-12-08 | Neorx Corporation | Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells |
US5595722A (en) | 1993-01-28 | 1997-01-21 | Neorx Corporation | Method for identifying an agent which increases TGF-beta levels |
US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5856340A (en) * | 1995-02-28 | 1999-01-05 | Eli Lilly And Company | Method of treating estrogen dependent cancers |
DE19604231A1 (en) * | 1996-01-29 | 1997-07-31 | Schering Ag | Combined pharmaceutical preparation and its use for the treatment of gynecological disorders |
TW442286B (en) * | 1996-02-28 | 2001-06-23 | Pfizer | New therapeutic uses of estrogen agonists |
IL120266A (en) | 1996-02-28 | 2005-05-17 | Pfizer | Use of estrogen antagonists and estrogen agonists in the preparation of medicaments for inhibiting pathological conditions |
AU6959898A (en) * | 1997-04-11 | 1998-11-11 | David J. Grainger | Compounds and therapies for the prevention of vascular and non-vascular pathol ogies |
US6054446A (en) | 1997-12-24 | 2000-04-25 | Sri International | Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use |
US6649645B1 (en) * | 1998-12-23 | 2003-11-18 | Pharmacia Corporation | Combination therapy of radiation and a COX-2 inhibitor for treatment of neoplasia |
CA2372720C (en) | 1999-05-04 | 2007-09-11 | John Antony Kanis | Androgen glycosides and androgenic activity thereof |
DE60106293T2 (en) * | 2000-10-25 | 2005-11-17 | Eli Lilly And Co., Indianapolis | METHOD OF INHIBITING CATARACTS |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
US5075321A (en) * | 1987-03-24 | 1991-12-24 | University Of Pennsylvania | Methods of treating diseases characterized by interactions of IgG-containing immune complexes with macrophage Fc receptors using antiestrogenic benzothiophenes |
US5395842A (en) * | 1988-10-31 | 1995-03-07 | Endorecherche Inc. | Anti-estrogenic compounds and compositions |
JP3157882B2 (en) * | 1991-11-15 | 2001-04-16 | 帝国臓器製薬株式会社 | New benzothiophene derivatives |
-
1993
- 1993-12-21 US US08/170,946 patent/US5451589A/en not_active Expired - Lifetime
-
1994
- 1994-12-19 RU RU94045272/14A patent/RU94045272A/en unknown
- 1994-12-19 KR KR1019940034924A patent/KR950016733A/en not_active Application Discontinuation
- 1994-12-19 NO NO944917A patent/NO944917L/en not_active Application Discontinuation
- 1994-12-19 SI SI9430406T patent/SI0662325T1/en unknown
- 1994-12-19 CA CA002138500A patent/CA2138500A1/en not_active Abandoned
- 1994-12-19 AT AT94309469T patent/ATE207748T1/en not_active IP Right Cessation
- 1994-12-19 JP JP6314601A patent/JPH07215867A/en active Pending
- 1994-12-19 IL IL11204994A patent/IL112049A0/en unknown
- 1994-12-19 AU AU81532/94A patent/AU8153294A/en not_active Abandoned
- 1994-12-19 DK DK94309469T patent/DK0662325T3/en active
- 1994-12-19 HU HU9403654A patent/HUT71228A/en unknown
- 1994-12-19 DE DE69428877T patent/DE69428877T2/en not_active Expired - Fee Related
- 1994-12-19 ES ES94309469T patent/ES2162844T3/en not_active Expired - Lifetime
- 1994-12-19 EP EP94309469A patent/EP0662325B1/en not_active Expired - Lifetime
- 1994-12-19 PT PT94309469T patent/PT662325E/en unknown
- 1994-12-19 ZA ZA9410097A patent/ZA9410097B/en unknown
- 1994-12-19 CZ CZ943216A patent/CZ321694A3/en unknown
- 1994-12-19 CN CN94119729A patent/CN1107702A/en active Pending
-
1995
- 1995-05-17 US US08/442,918 patent/US5760060A/en not_active Expired - Fee Related
- 1995-05-17 US US08/442,917 patent/US5719165A/en not_active Expired - Fee Related
- 1995-05-17 US US08/442,919 patent/US5843962A/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
DK0662325T3 (en) | 2001-12-03 |
EP0662325A2 (en) | 1995-07-12 |
US5760060A (en) | 1998-06-02 |
PT662325E (en) | 2002-03-28 |
CZ321694A3 (en) | 1995-08-16 |
RU94045272A (en) | 1996-10-20 |
KR950016733A (en) | 1995-07-20 |
US5843962A (en) | 1998-12-01 |
SI0662325T1 (en) | 2002-06-30 |
JPH07215867A (en) | 1995-08-15 |
AU8153294A (en) | 1995-06-29 |
ES2162844T3 (en) | 2002-01-16 |
NO944917D0 (en) | 1994-12-19 |
EP0662325A3 (en) | 1995-10-11 |
US5451589A (en) | 1995-09-19 |
ZA9410097B (en) | 1996-06-19 |
CA2138500A1 (en) | 1995-06-22 |
IL112049A0 (en) | 1995-03-15 |
NO944917L (en) | 1995-06-22 |
HU9403654D0 (en) | 1995-02-28 |
DE69428877D1 (en) | 2001-12-06 |
EP0662325B1 (en) | 2001-10-31 |
HUT71228A (en) | 1995-11-28 |
US5719165A (en) | 1998-02-17 |
ATE207748T1 (en) | 2001-11-15 |
DE69428877T2 (en) | 2002-04-25 |
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